Recent thymic emigrants (RTEs) are the youngest T cells in the lymphoid periphery, and are crucial for seeding the neonatal lymphoid periphery and for reconstituting the nave T cell pool in adults receiving umbilical cord blood or recovering frm lymphoablative viral infection or therapy. By identifying RTEs as GFP+ peripheral T cells in RAG2p-GFP transgenic mice, we have shown that RTEs undergo phenotypic and functional maturation for the first 3 weeks of residence in the periphery. During this transitional period, RTEs in both mice and humans exhibit diminished proliferation and altered cytokine secretion upon stimulation with antigen. The goal of the proposed experiments is to understand the basis for this evolutionarily conserved and developmentally regulated period of depressed immune function. We will test the hypothesis, based on strong preliminary data, that RTEs respond to low affinity ligands by acquiring both the capacity to invade tissues (thereby gaining exposure to self-antigens) and a heightened sensitivity to tolerance induction. We will use diabetes induction and allogeneic pregnancy to understand the benefits of post-thymic maturation in enforcing T cell tolerance to extrathymic antigens, and tumor eradication to explore its risks. Experiments proposed in this competitive renewal are encompassed by the following specific aims: Specific Aim 1: To compare the response of RTEs and mature T cells encountering peripheral self- antigen. These experiments will test the hypothesis that, compared to mature T cells, RTEs are invasive yet prone to tolerance upon recognition of self-antigens of varying affinities in a diabetes model system. Specific Aim 2: To compare the response of RTEs and mature T cells encountering tumor antigens of varying affinity. These experiments will test the hypothesis that, compared to mature T cells, RTEs are invasive yet prone to tolerance upon recognition of ligands of varying affinity in transplantable and spontaneous tumor model systems. Specific Aim 3: To explore regulatory T cell (Treg) induction and Treg sensitivity of RTEs. These experiments will determine whether enhanced induction of Tregs and/or sensitivity to Treg-mediated suppression impact RTE function. Enhancing our understanding of post-thymic maturation will help us anticipate the downstream impact, both positive and negative, of boosting immune function at this stage of T cell development, a worthy goal for improving vaccination strategies in neonates, enhancing anti-tumor responses following radio- or chemo- therapy, and promoting the recovery of T cell function in HIV infected individuals post-retroviral therapy.